Elacestrant Plus Abemaciclib Demonstrates Clinical Benefit in Pretreated ER+/HER2– Metastatic Breast Cancer

Elacestrant plus abemaciclib in

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Elacestrant (Orserdu) in combination with abemaciclib (Verzenio) demonstrated clinical activity and was well tolerated in patients with estrogen receptor (ER)–positive, HER2-negative metastatic breast cancer who received prior treatment with endocrine therapy and another CDK4/6 inhibitor, according to data from the phase 1b/2 ELECTRA trial (NCT05386108) presented at the 2024 ESMO Congress.

Findings showed that evaluable patients treated across 3 cohorts in phase 1b (n = 23) experienced an objective response rate (ORR) of 26%, which included 1 complete response (CR) and 5 partial responses (PRs). The clinical benefit rate (CBR) at 16 weeks and 24 weeks was 70% and 57%, respectively.

Regarding safety, no grade 4 adverse effects (AEs) were reported, and no grade 3 diarrhea was observed. Neutropenia was mainly attributed to abemaciclib.

“The combination was well tolerated and consistent with the known safety profile of abemaciclib and standard endocrine therapy,” lead study author Eva M. Ciruelos, MD, PhD, of Hospital Universitario 12 de Octubre in Madrid, Spain, and colleagues wrote in a poster presentation of the data.

Eligibility Criteria and Study Design

The phase 1b portion of ELECTRA enrolled patients at least 18 years of age with confirmed ER-positive, HER2-negative advanced or metastatic breast cancer. Prior therapy requirements in the metastatic setting included at least 1 line of endocrine therapy, no more than 2 lines of chemotherapy, and no more than two CDK4/6 inhibitors, excluding abemaciclib. Additionally, patients needed documented intra- or extracranial radiological progression during or after their most recent therapy and an ECOG performance status of 0 to 2. The presence of brain metastases was not required for phase 1b enrollment; however, patients who enroll in phase 2 will be required to have brain metastases at baseline.

Patients were excluded from phase 1b if they required immediate central nervous system–specific treatment; had leptomeningeal metastases; were treatment naive in the metastatic setting; had imminent organ failure and/or visceral crisis; or had prior treatment with abemaciclib, elacestrant, or investigational selective estrogen receptor degraders in the metastatic setting.

During the phase 1b portion of ELECTRA, patients were assigned to 1 of 3 treatment cohorts. Those in cohort 1 (n = 8) received elacestrant at 258 mg per day plus abemaciclib at 100 mg twice per day; patients in cohort 2 (n = 7) were given elacestrant at 345 mg once per day plus abemaciclib at 100 mg twice per day; and those in cohort 3 (n = 12) received elacestrant at 345 mg once per day plus abemaciclib at 150 mg twice per day.

The primary end point of phase 1b was to determine the recommended phase 2 dose (RP2D), which was determined to be 345 mg of elacestrant per day plus 150 mg of abemaciclib twice per day. The rate of dose-limiting toxicities in the first 28 days of treatment was also a primary end point. ORR per RECIST 1.1 criteria in patients with ER-positive, HER2-negative metastatic breast cancer with brain metastases will serve as the primary end point in phase 2.

Baseline Patient Characteristics

Among the patients enrolled in the phase 1b portion of the study, the median age of was 44 years (range, 32-67) in cohort 1, 51 years (range, 41-71) in cohort 2, and 54 years (range, 48-73) in cohort 3. All patients were female, all received a prior CDK4/6 inhibitor in the advanced/metastatic setting, and no patients had brain metastases. The majority of patients had an ECOG performance status of 0 (cohort 1, 80%; cohort 2, 57%; cohort 3, 58%), and had visceral metastases (80%; 86%; 75%),

Primary endocrine resistance was observed in 40% of patients in cohort 1, 14% of those in cohort 2, and 25% of patients in cohort 3. The median number of prior therapies for advanced or metastatic breast cancer was 2 (range, 1-3) for cohort 1, 2 (range, 1-4) for cohort 2, and 2 (range, 1-6) for cohort 3.

Prior lines of endocrine therapy in the advanced/metastatic setting included 1 (cohort 1, 60%; cohort 2, 43%; cohort 3, 42%), 2 (40%; 43%; 50%), or 3 (0%; 14%; 8%). Prior endocrine therapies included fulvestrant (Faslodex; 80%; 71%; 75%), an aromatase inhibitor (40%; 71%; 75%), tamoxifen (20%; 29%; 17%), and tamoxifen plus and aromatase inhibitor (0%; 14%; 8%). All patients received 1 prior line of chemotherapy except for 1 patient in cohort 3 who received 2 prior lines of chemotherapy.

ORR by Cohort and Additional Safety Data

In efficacy-evaluable patients in cohort 1 (n = 4), the ORR was 25% with 1 patient achieving a PR. One patient (25%) had stable disease (SD), and the CBR at week 16 was 50%. In cohort 2 (n = 7), the ORR was 29% with 2 PRs; the SD rate was 43%, and the CBR at week 16 was 71%. Patients in cohort 3 (n = 12), who were treated with the RP2D, achieved an ORR of 25%, including 1 CR and 2 PRs. Fifty-eight percent of patients had SD, and the CBR at week 16 was 75%.

In terms of safety, any-grade treatment-emergent adverse effects (TEAEs) were observed in 60% of patients in cohort 1 (n = 5), 86% of patients in cohort 2 (n = 7), and 92% in cohort 3 (n = 12). The rates of grade 3 TEAEs were 20%, 29%, and 58%, respectively.

The most common any-grade TEAEs included diarrhea (cohort 1, 60%; cohort 2, 86%; cohort 3, 92%), nausea (100%; 71%; 67%), neutropenia/decreased neutrophil count (20%; 43%; 67%), asthenia (20%; 43%; 42%), upper abdominal pain (0%; 0%; 42%), anemia (0%; 29%; 33%), vomiting (20%; 43%; 33%), increased gamma-glutamyltransferase (20%; 14%; 25%), and rash (0%; 0%; 25%).

Reference

Ciruelos E, Hamilton E, Kim SB, et al. Elacestrant in combination with abemaciclib in patients (pts) with brain metastasis (mets) from estrogen receptor-positive (ER+), HER2-negative (HER2-) breast cancer: Preliminary data from ELECTRA, an open-label, multicenter, phase 1b/2 study. Presented at: 2024 ESMO Congress; September 13-17, 2024; Barcelona, Spain. Abstract 364P.